tbuckley/cabot-search huggingface dataset:
INNV-01. ASSESSMENT OF SURVIVAL AND SAFETY FOLLOWING INTRATHECAL CHEMOTHERAPY VIA OMMAYA RESERVOIR FOR PATIENTS WITH LEPTOMENINGEAL DISEASE
Authors: Ehab Harahsheh, Shiv Shah, Richard Butterfield, Carl Ariete, Mark Lyons, Chandan Krishna, Richard Zimmerman, Shannon Fortin-Ensign, Bernard Bendok, Maciej Mrugala
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Leptomeningeal disease (LMD) carries poor prognosis with an average survival of 3-6 months after diagnosis. Ommaya reservoirs (OR) are an accessible alternative to serial lumbar punctures for delivery of intrathecal chemotherapy (IC) and disease monitoring but are not widely used. Intraventricular administration of chemotherapy may be associated with superior efficacy and improved patient comfort. The purpose of this study was to assess safety and efficacy of IC and disease monitoring via OR in routine clinical practice. METHODS Patients who received at least one administration of IC via OR for LMD between 2017 and 2022 were included. Demographics, treatment type, complications and outcomes were recorded. RESULTS We identified 22 patients (17 females, 5 males) with mean age 50.9 ± 14.8 years. The primary tumors were: breast (12), leukemia (3), ovarian carcinoma (3), CNS lymphoma (1), urothelial carcinoma (1), spinal melanocytoma (1), and high-grade glioma (1). A total of 208 OR injections were performed [median was 9 OR injections per patient, interquartile range (IQR) (5, 13)]. Five patients (23%) experienced mild adverse events of grade 2 or lower by Common Terminology Criteria for Adverse Events. Overall risk of adverse event from injection was 3.4% (7/208). Eight patients (36.3%) converted into negative CSF cytology (median 1 month following first injection). Eighteen patients (82%) had clinical or radiological progression of their LMD (median 2 months following first injection). Eleven patients (50%) died of their LMD during follow-up. Median OS and PFS from the first injection were 5.3 months [95% CI 4.8-NE (not estimable)] and 4.3 months [95% CI 1.8-16.0], respectively. CONCLUSION Use of OR in routine clinical practice is a safe and feasible option and should be strongly considered for treatment and monitoring of patients with LMD. The median OS in our cohort is comparable to prior published series.
NCOG-30. ENVIRONMENTAL ENRICHMENT AND HEALTH OUTCOMES AFTER RADIATION
Authors: Karl Cristie Figuracion, Tresa McGranahan, Frances Lewis, Christine Mac Donald, David Hunt, Jason Rockhill, Lia Halasz, Myron Goldberg, Hilaire Thompson
Journal: Neuro-Oncology (2023)

Abstract Individuals treated with brain radiation (RT) are at a disproportionately increased risk of accelerated aging and symptom burden. The aim of this abstract is to describe the health outcomes experienced by brain tumor (BT) survivors who received Photon (XRT) and Proton-Beam (PBRT) in relation to levels of environmental enrichment (EE). The study employed a cross-sectional cohort design among persons with glioma (WHO Grade 2 and 3) treated with RT approximately 5 years following diagnosis. EE consists of social network/engagement, physical activity, and employment status/financial stability measured by the Berkman-Syme Social Network Index, International Physical Activity Questionnaire, Vocational Index Scale, and two Socioeconomic Questions, respectively. EE level is classified into low, moderate, or high tertile. Montreal Cognitive Assessment measured cognitive function. Cortical atrophy is measured using temporal brain MRI images from the time of diagnosis, 3 years after, and at the time of enrollment. Images were processed using FreeSurfer. MD Anderson Symptom Inventory – BT module was used to measure functional status. Two-Way ANOVA described the health outcomes among individuals who received XRT and PBRT. Thirty-nine participants, 18 with astrocytoma and 19 with oligodendroglioma, completed the study protocol. Eighteen individuals received XRT (5 were categorized into Low EE, 10 to Moderate EE and 3 had High levels of EE) and 21 received PBRT (8 were categorized into Low EE, 7 had Moderate EE and 6 had High EE). Individuals who received XRT and had High levels of EE had higher scores in MoCA, lower cortical atrophy rate, and lower symptom burden than individuals who had Moderate and Low EE. BT survivors are at an increased risk of accelerated aging and progressive neurological decline. Providing an enriched environment may serve to reduce symptom burden, promote healthy brain aging, and improve cognitive and functional status in BT survivors receiving radiation.
IMMU-22. BLOCKADE OF CD47 RESULTS IN METABOLIC REPROGRAMMING TO ENHANCE IMMUNE CELL-MEDIATED CYTOTOXICITY OF GLIOBLASTOMA
Authors: Yu-Ting Tsai, Glenn Lesser, David R Soto-Pantoja
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most aggressive and malignant brain tumor. There is growing interest in using immunotherapy to treat GBM, however, clinical trials with immune checkpoints have shown little efficacy, likely due to significant GBM-associated systemic and intra-tumoral immunosuppression. The expression of the transmembrane protein CD47 contributes significantly to immunosuppression limiting innate and adaptive anti-tumor responses. Our new data shows that patient biopsies showed strong immunoreactivity to CD47 in GBM compared to normal adjacent tissue. Furthermore, high CD47 expression in GBM patients resulted in poor survival, indicating that CD47 may be a potential target for GBM treatment. Beyond the “don’t eat me signal”, CD47 facilitates its intracellular signaling through PLIC1 and it still unknown how CD47-related can influence metabolic reprogramming in the tumor microenvironment. Previous studies that upregulated fatty acid oxidation (FAO) provide GBM cells with metabolic plasticity to accommodate its dynamic nutrient microenvironment. Respirometry data revealed that blocking CD47 in murine cell line (CT2A) reduces mitochondrial function and ATP production by over 40-50% respectively (p*&amp;lt; 0.02). The reduction in mitochondrial respiration is linked to an over 50% reduction in FAO (*p&amp;lt; 0.004). This was associated with significant decreases in CPT1a, FASN, ATGL, and CD36 indicating a reduction in FA metabolism mediators. On the other hand, blocking CD47 on murine microglia (SIMA9), showed an opposite result from cancer cells, with increasing mitochondrial respiration and FAO. Initial shows differential responses may be due to the engagement of PLIC1 to CD47. Furthermore, blocking CD47 on microglia increased three-fold of the immune cell-mediated GBM cell cytotoxicity (*p&amp;lt; 0.005), suggesting that metabolic reprogramming associated with CD47 blockade could result in the improvement of immune adaptive responses in the GBM microenvironment. Taken together, our data indicated that CD47 blockade may be a prospective treatment to reduce GBM metabolic plasticity and increase microglia-mediated GBM killing.
EPCO-34. IMAGE-BASED PHENOTYPIC HIGH-CONTENT CRISPR-CAS9 SCREEN FOR CHARACTERIZING CANCER DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Samir Amin, Amit Gujar, Eunhee Yi, Wonyeong Kang, Megan Costa, Paul Gabriel, Greg Sjogren, Leigh Maher, Charles Lee, Paul Robson, Peter Dickinson, Rebecca Packer, Elise Courtois, Roel Verhaak
Journal: Neuro-Oncology (2023)

Abstract The genomic landscape of pediatric high-grade glioma is characterized by a high level of aneuploidy but few focal amplifications or homozygous deletions. Cancer aneuploidies are the principal source of tumor heterogeneity driving tumor growth and therapy resistance. Here, we deployed an image-based phenotypic high-content CRISPR-Cas9 screen to identify aneuploidy-associated pediatric glioma driver genes. Through integrated computational analyses combining whole-genome sequencing datasets from 106 pediatric gliomas and 81 canine gliomas, we identified a set of 460 genes present in regions of aneuploidy in both diseases. We designed a custom guideRNA library to systemically knockout the 460 gene set using an arrayed CRISPR-Cas9 knockout screen in two pediatric high-grade glioma cell lines. By deploying 72 of 384-well plates on automated confocal Opera Phenix High-Content Screening System and dyes staining cell membrane, nucleus, and apoptotic cells, we established 5 million live-cell images across three timepoints (day 7, 8, 9 post-transduction). Each gene was randomized to 32 randomized wells across four 384-well plates to gather robust morphological profiles. Through image-based nucleus and cell segmentation workflow, we characterized 50 million single cells across 27,648 wells over three time points. Using semi-supervised machine learning methods, we derived 1,050 cell morphological features to characterize knockout phenotypes, e.g., viability, growth, and morphology (size, shape, texture of nucleus and cells) across cells. The top ranked genes were then linked to oncogenes and tumor suppressors based on pathway and ontology analysis as well as functional in vitro and in silico validation using Pediatric Cancer Dependency Map. We find convergence of the most impactful molecular abnormalities - based on their knockout phenotypes - on candidate signaling pathways for the development of new drugs and repurposing of existing drugs for pediatric high-grade glioma.
RADT-18. PROTON CRANIOSPINAL IRRADIATION WITH CHECKPOINT INHIBITOR THERAPY FOR PATIENTS WITH LEPTOMENINGEAL DISEASE FROM SOLID TUMORS – A SINGLE INSTITUTION CASE SERIES
Authors: Ugur Sener, Mason Webb, William Breen, Nadia Laack, David Routman, Paul Brown, Anita Mahajan, Kelsey Frechette, Konstantinos Leventakos, Arkadiusz Dudek, Svetomir Markovic, Sani H Kizilbash, Jian Campian
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes. METHODS In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors. RESULTS Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis. CONCLUSION Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.
TMIC-80. PERK CONTRIBUTES TO GLIOBLASTOMA PROGRESSION BY REGULATING GLIOBLASTOMA STEM CELL ADAPTATION TO EXTRA CELLULAR MATRIX STIFFENING THROUGH F-ACTIN REMODELING AND FOCAL ADHESION COMPLEX REGULATION
Authors: Mohammad Khoonkari, Dong Liang, Chris Govaerts, Romy Huurman, Marleen Kamperman, Patrick van Rijn, Frank Kruyt
Journal: Neuro-Oncology (2023)

Abstract The association between a stiffening extracellular matrix (ECM) and increased aggressiveness of gliomas is well established. Originally recognized as a protective mechanism against endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) is primarily responsible for maintaining cellular protein homeostasis and triggering cell death under severe stress conditions. However, emerging evidence indicates that the ER transmembrane UPR sensors, IRE1 and PERK, possess additional functions beyond proteostasis, such as modulating cancer stem cell differentiation, cell adhesion, and migration, which also involve more recently identified protein scaffold functions. In this study, we uncover a novel role of PERK in cellular adaptation to matrix stiffening. Glioblastoma stem cells (GSCs), when cultured on human blood plasma/alginate hydrogels with tuneable stiffness, exhibited stiffness-dependent cellular responses, including cell flattening, differentiation, and enhanced migration. Through genetic depletion and pharmacological inhibition strategies combined with immunofluorescence microscopy, we identified the involvement of a previously found PERK/FLNA signaling mechanism in the adaptive response to matrix stiffness, where F-actin polymerization emerged as a key mechanism. To explore the possible involvement of PERK in sensing ECM stiffness, the expression of various proteins that constitute the focal adhesion complex were studied. Remarkably, PERK also influenced the maturation of focal adhesion complexes components know to be involved in sensing ECM stiffness. Finally, comparative transcriptional profiling of PERK proficient and deficient GSCs uncovered significant alterations in the expression of genes associated with cell adhesion and extracellular matrix (ECM)-related processes. These findings reveal a novel function of PERK in stiffness-dependent cellular adaptations, with ongoing investigations exploring the underlying molecular mechanisms and therapeutic implications for glioblastoma progression
QOL-26. A RANDOMIZED, DOUBLE-BLIND PHASE 3 STUDY OF VORASIDENIB VS PLACEBO IN PATIENTS WITH MUTANT <i>IDH1/2</i>DIFFUSE GLIOMA (INDIGO): ANALYSIS OF HEALTH-RELATED QUALITY OF LIFE, NEUROCOGNITION AND SEIZURES
Authors: Katherine Peters, Ingo Mellinghoff, Martin van den Bent, Deborah Blumenthal, Mehdi Touat, Jennifer Clarke, Joe Mendez, Shlomit Yust-Katz, Warren Mason, Francois Ducray, Yoshie Umemura, L Burt Nabors, Matthias Holdhoff, Andreas Hottinger, Yoshiki Arakawa, Juan Sepúlveda, Wolfgang Wick, Riccardo Soffietti, James Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth Maher, Andrew Bottomley, Dan Zhao, Shuchi Pandya, Lori Steelman, Islam Hassan, Patrick Wen, Timothy Cloughesy
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The Phase 3 INDIGO study (NCT04164901) is a randomized, double-blind evaluation of vorasidenib, an oral, brain-penetrant inhibitor of mutant isocitrate dehydrogenase (mIDH) 1/2 enzymes, compared with placebo, in patients with grade 2 mIDH1/2 diffuse gliomas, whose only prior treatment was surgery. The primary endpoint, radiographic progression-free survival by blinded independent review committee, and the key secondary endpoint, time-to-next-intervention, were significantly improved with vorasidenib versus placebo. As these patients are young, with several years’ life expectancy, impact of treatments on health-related quality of life (HRQoL), cognition and symptomatic burden is of interest. METHODS HRQoL, assessed by Functional Assessment of Cancer Therapy-Brain (FACTBr) questionnaire, was a secondary endpoint. FACT-Br was collected at baseline, Cycles 2 and 3, then every 3 months. Scores were interpreted using an estimate of clinically meaningful deterioration change from baseline for each arm. Exploratory endpoints included neurocognitive function, assessed by a validated battery of cognitive performance instruments, and seizure frequency and severity, assessed using a subject diary. RESULTS 331 patients were randomized to vorasidenib (n = 168) or placebo (n = 163) (median age, 40.0 years; Karnofsky performance scale = 100, 53.5%; ongoing medical history of seizures, 54.1%). Median follow-up was 14.2 months. No clinically meaningful deterioration from baseline FACT-Br total score and subscales were observed at any timepoint through the median treatment duration (Cycle 13) in either arm. At baseline, active seizures (≥ 1 seizure in the previous 30 days) were reported in 20/168 (11.9%) vorasidenib patients and 20/163 (12.3%) placebo patients. On-treatment seizure frequencies and cognition outcomes will be presented by arm. CONCLUSION INDIGO is the first randomized Phase 3 study of targeted therapy in grade 2 mIDH1/2 diffuse glioma. HRQoL, as measured by FACT-Br, was maintained during treatment with vorasidenib. These data support the clinical benefit of vorasidenib in this patient population for whom chemotherapy and radiotherapy are being delayed.
CSIG-17. NICOTINAMIDE N-METHYLTRANSFERASE (NNMT) AS A POTENTIAL THERAPEUTIC TARGET FOR EGFRVIII-DRIVEN GLIOBLASTOMA
Authors: Ming Li, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract Nicotinamide N-methyltransferase (NNMT) is an enzymatic catalyst involved in converting methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM), generating S-adenosine hyperblastoids (SAH) and 1-methylnicotinamide (MNA). Increased NNMT expression is frequently observed in various cancers and is associated with tumor progression, metastasis, unfavorable clinical outcomes, and drug resistance. Notably, NNMT stands out as one of the most up-regulated metabolism-related genes in glioblastoma, although the underlying mechanism for its overexpression remains elusive. Glioblastoma commonly exhibits genetic lesions in the epidermal growth factor receptor (EGFR) gene, including amplification or mutation, with EGFRvIII being the predominant mutant contributing to glioblastoma cell proliferation, invasion, therapeutic resistance, metastasis, and stemness. In this study, we demonstrate that activation of wild-type EGFR by EGF or the constitutively active mutant EGFRvIII promotes NNMT expression and enzyme activity in established glioblastoma cell lines and glioblastoma stem-like cells via the p38 mitogen-activated protein kinase pathway. Additionally, we identify STAT1 as a downstream transcription factor essential for EGFR/EGFRvIII-induced NNMT upregulation. RNA interference-mediated knockdown of NNMT in glioblastoma cells significantly inhibits EGFRvIII-promoted invasion and proliferation in vitro. Targeting NNMT effectively suppresses EGFRvIII-driven glioblastoma tumorigenicity and prolongs the survival of tumor-bearing mice. Clinically, NNMT is highly expressed and positively correlated with EGFR expression in human glioblastoma tumors. Collectively, these findings establish NNMT as a previously unrecognized downstream target gene of EGFR/EGFRvIII expression and highlight its potential as a therapeutic target for inhibiting EGFRvIII-driven glioblastoma.
PATH-39. INTERPRETABLE IDH CLASSIFICATION FROM H&amp;E-STAINED HISTOLOGY SLIDES
Authors: Shubham Innani, Bhakti Baheti, MacLean P Nasrallah, Spyridon Bakas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Infiltrating gliomas are the most common primary adult brain tumors. Isocitrate dehydrogenase (IDH) mutation is a key driver of gliomagenesis in 25–30% of infiltrating gliomas and correlates with favorable prognosis when compared with the histologically-similar but biologically-distinct IDH-wildtype glioblastoma. We sought an interpretable computational pipeline to predict IDH status from digitized histopathology glioma sections (Whole Slide Images - WSI) and identify associated cell-level morphology. Materials and METHODS We identify 799/1122 TCGA-GBM and TCGA-LGG tumors (1534 WSIs) with available IDH status. 379 of these tumors (756 WSI) are IDH-wildtype and 420 tumors (778 WSI) are IDH-mutant. Each H&amp;E-stained WSI undergoes comprehensive curation to remove artifactual content before classification. Our interpretability mechanism is based on weakly-supervised attention-based multiple-instance-learning. IDH-associated morphology in each WSI is evaluated by a HoverNet model from the 50 highest-attention tiles. Classification performance was assessed using 10-fold cross-validation, with training (80%), validation (10%), and test (10%) sets stratified on the patient/tumor level, without controlling for grade. An additional out-of-sample hold-out test set of 82 IDH-wildtype and 32 IDH-mutant tumors from the University of Pennsylvania Health System was further used for independent evaluation. RESULTS Quantitative performance evaluation revealed AUC=0.92 and Balanced Accuracy=0.84 on the TCGA test set, and AUC=0.88 and Balanced Accuracy=0.80 on the independent hold-out UPenn set. When comparing identified IDH-wildtype with IDH-mutant tumors (and while excluding glioblastoma with lower-grade histology), the former shows significantly (p&amp;lt; 0.00005) higher distribution of neoplastic and necrotic cells and significantly (p&amp;lt; 0.00003) lower distribution of inflammatory and connective cell type tissue. CONCLUSION Histological prediction of IDH status represented an ideal prototype to interrogate WSI towards identifying clinically-relevant tumor biomarkers. Detailed interpretation of results reveals computational predictions being driven by human-identifiable features at the patch level. This study robustly identifies morpho-IDH correlates and could enable further prognostic refinement of patients.
TMIC-10. TGF-Β2 DRIVEN SURVIVAL IN DMG AND GBM
Authors: Vuong Trieu
Journal: Neuro-Oncology (2023)

Abstract OT-101 is being developed as immunotherapy for a broad range of cancers. Cancers overexpress TGF-β, which suppresses host innate immune response to the cancers. Treatment with OT-101 lifts the TGF-β cloaking effect and allows innate or therapeutic immunity to attack and eliminate the cancers. OT-101 completed phase 2 for pancreatic cancer and melanoma and phase 2 in glioblastoma with robust efficacy and safety. Here we are presenting data and clinical trial design for OT-101 in DMG (Diffuse Midline Glioma). ADME studies were performed on OT-101 demonstrating perfusion of the brain including the midline by either intracerebral or intraventricular administration. The studies allowed us to bridge intraventricular administration to corpus of CED administered OT-101. Safety studies were performed in two species supporting the safety of OT-101 intraventricular administration. Expression analyses of pediatric brainstem cases of the TCGA database yielded highly significant survival benefit across all four quartiles of TGF-β2 expression. This was not observed for either TGF-β1 and less so for TGF-β3. Expression analyses of all gliomas treated with radiation yielded highly significant survival benefit across all four quartiles of TGF-β2 expression. This was not observed for either TGF-β1 nor TGF-β3. In adult gliomas, OT-101 is noninferior to the most active drugs (TMZ, BCNU, or PCV) in both chemo naïve and chemo-resistant patients. In terms of overall survival when compared to standard chemotherapy (TMZ, BCNU, or PCV) in both G004 and G005 as both the hazard ratio, which was 0.9168, and the 90% upper limit of the confidence interval, which was 1.2245, were both less than the initial non-inferiority bound of 1.25. Together the data support the development of OT-101 for DMG. The phase 2 clinical trial design is being presented for OT-101 in DMG administered using Ommaya reservoir following radiation in newly diagnosed DMG